Recent research has identified several proteins with potent anti-arthritic properties. Recombinant proteins, though, have limited half-lives in vivo and require repeated injection or infusion, daily in some cases, to maintain efficacy. Through the use of gene transfer, it is possible to deliver cDNAs encoding such proteins to the synovial lining of joints and enable their persistent production and secretion for extended periods. To achieve this, we have been exploring the use of lentiviral vectors, which are capable of efficient and stable genetic modification of target cells in vivo. The unique abilities of this vector system make it an extremely promising candidate for direct intra-articular gene transfer for the treatment of chronic joint diseases. In pilot studies, we found that recombinant lentiviral vectors were capable of generating extraordinarily high levels of intra-articular transgene expression in the knees of rats, and enabled stable expression of a therapeutic gene product for at least 6 months. The current proposal requests funds to support further research and development of lentiviral vectors for a gene based therapy for arthritis. The study will address three issues central to consideration of commercial development: 1) therapeutic efficacy, 2) vector dosing in proportional target joints and 3) generation of a lentiviral packaging line for large-scale production. It is intended that the results of these studies will establish the feasibility of lentiviral mediated gene delivery for treatment of arthritis.